Update on biology and managementof mesothelioma

Rachelle Asciak1,2, Vineeth George 1 and Najiib M. Rahman1

Number 2 in the Series “Thoracic oncology”Edited by Rudolf Huber and Peter Dorfmüller

Affiliations: 1Oxford Centre for Respiratory Medicine, University Hospitals NHS Foundation Trust, Oxford, UK.2Mater Dei Hospital, Msida, Malta.

Correspondence: Rachelle Asciak, Oxford Centre for Respiratory Medicine, Oxford University Hospitals NHSTrust, Churchill Hospital, Oxford, OX3 7LE, UK. E-mail: rachelle.asciak@ouh.nhs.uk

@ERSpublicationsDespite a better understanding of the pathogenesis of malignant pleural mesothelioma, effectivetreatment that prolongs survival significantly is lacking. Ongoing research may identify select patientgroups that may benefit from surgical treatment. https://bit.ly/3k16J9O

Cite this article as: Asciak R, George V, Rahman NM. Update on biology and managementof mesothelioma. Eur Respir Rev 2021; 30: 200226 [https://doi.org/10.1183/16000617.0226-2020].

ABSTRACT Malignant pleural mesothelioma is an aggressive, incurable cancer that is usually caused byasbestos exposure several decades before symptoms arise. Despite widespread prohibition of asbestosproduction and supply, its incidence continues to increase. It is heterogeneous in its presentation andbehaviour, and diagnosis can be notoriously difficult. Identification of actionable gene mutations hasproven challenging and current treatment options are largely ineffective, with a median survival of10–12 months. However, the past few years have witnessed major advances in our understanding of thebiology and pathogenesis of mesothelioma. This has also revealed the limitations of existing diagnosticalgorithms and identified new treatment targets.

Recent clinical trials have re-examined the role of surgery, provided new options for the management ofassociated pleural effusions and heralded the addition of targeted therapies. The increasing complexityof mesothelioma management, along with a desperate need for further research, means that amultidisciplinary team framework is essential for the delivery of contemporary mesothelioma care.

This review provides a synthesised overview of the current state of knowledge and an update on thelatest research in the field.

IntroductionMalignant pleural mesothelioma (MPM) is an aggressive and incurable malignancy that originates fromthe mesothelial cells that form the serosal lining of the pleural cavity. The median age at diagnosis is75 years, and overall survival is 38% at 1 year and 7% at 3 years, reflecting the poor prognosis [1]. Despitethe increasing prohibition of asbestos production and supply over the past 30–40 years, deaths from MPMcontinue to rise [2].

Histologically, there are three types of mesothelioma: epithelioid (∼60%), sarcomatoid (20%) andbiphasic (20%), which has both epithelioid and sarcomatoid features [3], with median survival of 19, 4

Copyright ©ERS 2021. This article is open access and distributed under the terms of the Creative Commons AttributionNon-Commercial Licence 4.0.

Provenance: Commissioned article, peer reviewed.

Previous articles in this series: No. 1: Eichhorn F, Winter H. How to handle oligometastatic disease in nonsmall celllung cancer. Eur Respir Rev 30: 2021; 200234.

Received: 10 July 2020 | Accepted after revision: 27 Oct 2020

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and 12 months, respectively, in a database of 1183 patients with mesothelioma [4]. Treatment withchemotherapy doublet cisplatin/pemetrexed can extend life by ∼2–3 months, with longer median time toprogressive disease (6 versus 4 months). Response rates to cisplatin/pemetrexed were 41% in clinical trialsettings [5], but 26.3% in a subsequent nonrandomised study of 1704 patients [6]. Where licensed,bevacizumab is added to this regime since cisplatin/pemetrexed/bevacizumab combination was associatedwith median (95% CI) survival of 19 (16–22) months, versus 16 (14–18) months with cisplatin/pemetrexed alone [7], with grade 3–4 adverse events occurring in 71% versus 62%, respectively [7]. Anumber of patients will not be fit enough to receive first-line chemotherapy, and in addition, of thosewho do receive chemotherapy, many will risk the associated adverse effects of chemotherapy without anybenefit in terms of disease response. It would be ideal to predict the response or resistance to cancertreatment beforehand, so that patients who are not likely to respond to treatment may be spared theassociated side-effects.

The mechanism of carcinogenesis is not fully understood, but most cases are attributable to asbestos fibreexposure and inhalation. The pathogenesis of MPM is thought to be multifactorial, and targeted therapieshave often proved to be unsuccessful in MPM. Therefore, a better understanding of the biology andpathogenesis of mesothelioma may enable identification of effective treatment targets, and facilitate thedevelopment of a personalised treatment approach.

The biology of mesotheliomaPathogenesisAsbestosMesothelioma was first characterised in 1931, but only linked to asbestos in a South Africanepidemiological study published in 1960 [8]. It is now recognised that 85% of mesothelioma in males isattributable to occupational exposure to asbestos, but only up to 10% of people with occupational exposureto asbestos develop mesothelioma [8, 9]. Asbestos exposure is also linked to lung cancer, and combinedcigarette smoking with asbestos exposure increases lung cancer risk from 10- to almost 100-fold comparedto unexposed people [10]. In contrast, cigarette smoking does not appear to be associated with increasedrisk of mesothelioma [11].

Asbestos had been used previously for pottery, but mass mining began in the 20th century when asbestoswas used to insulate against heat, fire and corrosion [10]. Some of the high-risk occupations includemechanics working on brake and clutch linings, construction and demolition workers, dockyard andshipyard workers, plumbers and electricians. Nonoccupational exposure may occur via exposure through ahousehold asbestos worker, and living near an asbestos factory. The use of asbestos was banned in theUnited Kingdom (UK) in 1999, and in all European Union countries in 2005, although compliance withthis directive has not been verified in some countries. Due to the long latency period of 30–40 yearsbetween first exposure and the development of mesothelioma [12], new mesothelioma cases are stilldiagnosed yearly. In addition, the inhabitants of countries that have banned asbestos correspond to 16% ofthe world population, and therefore currently the incidence of MPM is still increasing worldwide [10]. Inan epidemiology study published in 2014, the UK, the Netherlands, Malta and Belgium had the highestrates of mesothelioma in Europe [13]. In the UK, 84% of patients diagnosed with mesothelioma were maleand their cases were probably linked to occupational exposure [1].

Documenting and quantifying asbestos exposure is difficult, because it may not be recalled, may berecalled erroneously or recall may be motivated by the possibility of compensatory damages beingawarded. Furthermore, workers within the same workplace may be exposed to varying quantities and typesof asbestos. Nonoccupational exposure to asbestos may be present. There is high incidence ofmesothelioma in some families, where exposure to asbestos may be through the clothing of a familymember who is an asbestos worker, although the possibility that there is a genetic predisposition tomesothelioma has also been suggested, as discussed later [14, 15].

There are two main types of asbestos fibres: amphiboles (straight, long fibres, including amosite (brownasbestos), crocidolite (blue asbestos), anthophyllite and tremolite), and the more commonly usedserpentine (short, curly fibres), mainly chrysotile (white asbestos). Exposure to amphiboles carries a higherrisk of mesothelioma than chrysotile [16, 17]. Accessibility of amphiboles to the peripheral lung is higher,and biopersistence of amphiboles was noted in both animal and human studies with continuouslyincreasing levels of recoverable lung amphibole fibre levels, whereas chrysotile fibres are able to be partiallydigested and cleared from the lungs within months [18]. However, many patients will have been exposedto both amphibole and chrysotile asbestos [14].

Inhaled asbestos fibres reach the parietal pleura via the alveoli, visceral pleura and across the pleural space, orvia retrograde flow through the lymphatic vessels. Chronic inflammation precedes mesothelioma, and is

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mostly found around stomata and lymphoid patches in the basal parietal pleura, which is the most commonsite for mesothelioma [10]. MPM progresses from the parietal to the visceral pleura and invades surroundingtissues, with involvement of the visceral pleura denoting more advanced disease (higher stage on the eighthversion of the International Association for the Study of Lung Cancer (IASLC) staging system) [19].

The pathogenesis of mesothelioma is multifactorial. Crocidolite asbestos fibres induce toxicity in humanmesothelial cells in vitro in a dose-dependent manner [20]. This raises the question of how MPM developsif the asbestos fibres kill the mesothelial cells. Crocidolite has been shown to induce macrophageaccumulation within pleura and lung. Macrophages release tumour necrosis factor (TNF)-α upon contactwith crocidolite, and human mesothelial cells express TNF-α receptors. Additionally, asbestos causes thehuman mesothelial cells to secrete TNF-α. The TNF-α ligand–receptor interaction activates the NF-κBpathway, which allows the human mesothelial cells to divide rather than die, acquiring resistance toapoptosis [21]. If there is sufficient DNA abnormality caused by asbestos, then the mesothelial cells maydevelop into mesothelioma. Exposure to asbestos is thought to trigger several processes that ultimately leadto mesothelioma, which include the following.

1. Inhaled fibres cause irritation with subsequent repeated cycles of tissue damage and repair and localinflammation.

2. Direct physical interaction: asbestos fibres penetrate mesothelial cells and disrupt mitotic spindlesresulting in chromosomal abnormalities.

3. Mesothelial cells exposed to asbestos release inflammatory cytokines and growth factors, inducinginflammation and creating a pro-tumour microenvironment.

4. Macrophages phagocytose asbestos fibres, but their inability to digest them results in the production ofreactive oxygen species, leading to intracellular DNA damage and abnormal repair.

5. Mesothelial cell death as a result of asbestos leads to release of high mobility group box 1, whichfurther promotes and sustains chronic inflammation.

6. Phosphorylation of protein kinases leads to increased expression of proto-oncogenes, promotingabnormal cellular proliferation [22–24].

Other factorsThe majority of workers exposed to asbestos do not develop mesothelioma, and ∼20% of cases ofmesothelioma are not recognised to be associated with asbestos exposure [25]. In addition, mesotheliomadevelops in adults after a very long latency period, and there are rare cases of mesothelioma that arediagnosed in children [26], implying that mesothelioma in children either behaves very differently fromthe mesothelioma in adults, or is not associated with asbestos exposure in the same way. These findingssuggest that other factors, apart from asbestos, are involved.

Simian virus 40Simian virus 40 (SV40), a DNA tumour virus, is endogenous to the rhesus monkey, and is thought to haveinfected humans via contaminated polio vaccines in the 1950s and 1960s [27, 28], although SV40 was alsodetected in people who had not received the vaccine, indicating that other routes of infection exist [2, 22, 23].

SV40-like DNA sequences were found in up to 60% of human mesothelioma specimens in France and USA[29, 30], and similar results were also reported in an independent multilaboratory USA study (10 (83%) outof 12 mesotheliomas were found to have SV40 DNA sequences) and in several other laboratories worldwide[31, 32]. Furthermore, >50% of hamsters injected with SV40 developed mesothelioma [33]. In addition,human mesothelial cells were found to be more susceptible to SV40 infection and transformation thanfibroblasts and epithelial cells, with SV40 and asbestos found to be co-carcinogenic in vitro [20]. Conversely,SV40 was not found in Turkish (n=9) or Finnish (n=49) mesothelioma samples [34, 35], possibly related togeographical differences in distribution of administration of SV40-contaminated vaccines.

However, it has been suggested that in the above studies, the SV40 DNA sequences documented to havebeen found in mesothelioma represent false positives from contaminating plasmids resulting in positivesequencing results [36]. However, this would not explain the positive results in animal models.Consequently, the role of SV40 in mesothelioma remains controversial.

RadiationIonising radiation has been identified as a human carcinogen and risk factor for several cancer types.Cases of the development of mesothelioma after radiation exposure have been reported, with twoepidemiological studies showing increased risk of mesothelioma after radiation for testicular cancer(relative risk 4, 95% CI 2–8.1), and lymphoma (observed/expected ratio 2.3, 95% CI 1–4.3) [37–39].

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ErioniteThe high incidence of mesothelioma in Karain and Tuzkoy villages in Turkey is attributed to exposure toerionite, a mineral fibre commonly found in the stones of the houses in these villages [14, 40, 41].Mineralogical and pedigree analysis in these villages revealed that there may also be an autosomaldominant genetic susceptibility to mesothelioma [42]. In addition, there is evidence from animal modelsthat erionite is a more potent inducer of MPM than asbestos, with 40 (100%) out of 40 of rats injectedwith intrapleural erionite developing MPM, compared to 19 (47.5%) out of 40 of rats injected withintrapleural asbestos [43].

Genetic mutations in mesotheliomaThe identification of a specific gene mutation in mesothelioma would aid the development of targetedtherapy. However, mesothelioma is notoriously heterogeneous in its presentation, behaviour andaggressiveness, and its genetic make-up is no exception: a specific genetic mutation common to allmesothelioma has not been identified. DNA sequencing of 198 unrelated patients with mesotheliomarevealed that at least one germline mutation was present in 12%, and 25% of the mutations detected werein BAP1, 12.5% in BRCA2 and 8.3% in CDKN2A (the odds of having a mutation OR 1658, 95% CI 199–76224, p<0.001; OR 5, 95% CI 1–14.7, p 0.03; OR 53, 95% CI 6–249, p<0.001, respectively, compared withthe noncancer control population) [44].

The genes identified as being commonly mutated in MPM are those in the p53/DNA repair pathway(TP53, SMARCB1, BAP1) and PI3K-AKT pathway (PDGFRA, KIT, KDR, HRAS, PIK3CA, STK11, NF2),with the commonest being in BAP1, CDKN2A and NF2 [45–50]. In contrast, K-ras activation is rare inmesothelioma, suggesting that development of mesothelioma is not dependent on this pathway [51]. Theinterpatient variation of the mutational landscape for these genes highlights the potential importance ofpersonalised and targeted therapies in MPM.

The tumour suppressor genes exhibited nonsynonymous, stop codon gain and frameshift insertionmutations as identified by integrated genomic studies on MPM tumour samples [48]. The tumoursuppressor gene TP53 plays a central role in the response to DNA damage and induces cell apoptosis incells with DNA damage. Mutations in TP53 occur in >50% of all human cancers [52], and in ∼5–8% ofMPM [53, 54]. Mutated TP53 is associated with significantly decreased survival in MPM compared withwild-type TP53 [54]. Other frequent mutations in MPM are in the tumour suppressor NF2 in ∼50%, andthese are associated with increased proliferation and invasiveness of mesothelioma; and conversely, BAP1loss is present in ∼30–60% of MPM and is associated with improved prognosis [46, 55]. In addition, lossof INK4A/Arf in mice with MPM was associated with significantly reduced median survival and highlyinvasive tumours, suggesting that INK4A loss substantially contributes to the poor clinical outcome ofMPM [56]. Mutations in NF2 and INK4A, genes involved in apoptosis regulation, may explain, at least inpart, the resistance of mesothelioma to most conventional drugs, because the cells are resistant to theinduction of apoptosis.

Mesothelioma (n=106 mesothelioma samples in total) had the lowest percentage of samples with anactionable mutation out of 10945 tumour samples of varied primary malignancies. Those mesotheliomasamples that did have actionable mutations had the lowest level of actionability based on the identifiedmutation [50]. These studies further highlight the uphill struggle to identify clinically useful, more targetedtherapies for MPM despite the use of advanced techniques.

The management of mesotheliomaIn patients with MPM, the onset of disease is often insidious and the diagnosis difficult to make. Patientspredominantly present with dyspnoea, chest pain or both, and can often receive treatment for otherbenign conditions prior to the diagnosis being made [2, 12].

Current treatment options are relatively ineffective and median survival is 10–12 months [57]. However,early diagnosis in a multidisciplinary framework is key to limiting morbidity and prolonging survival.

Pathological confirmationThe diagnosis of MPM depends on positive pleural fluid cytology or histological confirmation via pleuralbiopsy [12]. Existing guidelines recommend thoracocentesis as the initial pleural procedure, andsensitivities as high as 73% have been reported based on audit data from single centres [12, 58]. However,more recent prospective studies have demonstrated that the diagnostic yield of pleural fluid cytology canbe as low as 0–6% for MPM [59, 60].

Consequently, pleural biopsies with appropriate immunohistochemistry are required for the vast majority ofcases [12, 61]. These can be obtained percutaneously under radiological guidance or under direct vision at

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thoracoscopy. Thoracoscopic biopsies from multiple sites remain the preferred approach, as the larger biopsysize generally increases diagnostic confidence and allows for histological subtyping [62]. In addition, deeperbiopsies allow for the assessment of tumour invasion by including fat and/or skeletal muscle [63].

Image-guided biopsies have been shown to be effective in diagnosing malignant pleural disease [64–66].However, there are limited data on their use specifically for mesothelioma and current guidelines highlightthat they are of particular value for patients who are unable to tolerate thoracoscopy [12].

More recently, confocal laser endomicroscopy (CLE) has been used to provide real-time imaging at acellular level. This technology has been used in other areas of medicine to increase diagnostic yield bydifferentiating malignant tissue from benign fibrosis. A recent feasibility study of 20 patients withsuspected MPM suggested that fluorescein-aided CLE could be used to differentiate epithelioid andsarcomatoid MPM from pleural fibrosis regardless of the biopsy method [67].

The recently concluded TARGET trial randomised patients who had an initial nondiagnostic computedtomography (CT)-guided percutaneous pleural biopsy to either a repeat procedure or a pleural biopsy fromareas of high 2-fluoro-2-deoxy-D-glucose uptake on CT-positron emission tomography (PET). Datapresented at the recent British Thoracic Society Winter Meeting demonstrated that there was no significantdifference in sensitivity for the diagnosis of MPM with the latter approach compared to standardCT-guided biopsy [68]. However, the full results are keenly awaited.

StagingA number of staging systems have been used for MPM [69]. The eighth edition of the IASLC tumour,node, metastasis (TNM) staging system, which was published in 2018, was developed using aninternational cohort study with data on almost 2000 patients with pathologically confirmed MPM [19].Disease stage using the TNM classification was shown to be a key predictor of survival in this populationand this is now the preferred system for MPM staging [12, 62].

A number of imaging modalities have been evaluated for the staging of MPM. However, all of thesecompare unfavourably to operative staging with mediastinoscopy to assess lymph node involvement [12].

CT (figure 1) of the chest and abdomen is considered the primary cross-sectional imaging modality and isthe mainstay of radiological staging. It is both widely used and easily accessible. However, it performspoorly when assessing locoregional soft tissue disease or nodal metastases [12]. Contrast-enhancedmagnetic resonance imaging (MRI) (figure 2) is better to evaluate chest wall and diaphragmatic invasion.One prospective case series of 76 patients who underwent radical surgery correlated radiological stagingwith final pathological staging [70]. In this setting, MRI revealed the presence of 17 (22%) unresectable T4or M1 tumours which were not identified by CT. However, over half the cases in this series werepathologically upstaged due to more advanced pericardial involvement, which was evident intraoperatively.Furthermore, the accuracy of MRI in assessing nodal disease was low with a reported sensitivity of 66% forassessing disease at stage N2 or less.

CT-PET has been shown to be superior to CT in identifying extrathoracic disease and is often used forassessing response to therapy [71, 72]. A small retrospective review suggested CT-PET was superior in

FIGURE 1 Computed tomographyscan image of the chest, withright-sided irregular and nodularpleural thickening in a case ofmalignant pleural mesothelioma.

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identifying nodal disease, with 14 out of 35 individuals upstaged, with a consequent decision not toproceed to surgery [73].

Surgical treatment optionsSurgery is controversial and limited to a small number of patients with early-stage disease. Research intoits utility has been hampered by varying definitions of surgical procedures and a heterogeneity of practice.However, the 2011 IASLC International Staging Committee and the International Mesothelioma InterestGroup consensus statement offered some clarity by defining procedures into four distinct groups (table 1)

a)

c)

b)

FIGURE 2 Axial magnetic resonance imaging (MRI) thorax images (T1 with contrast) demonstrate a) left-sided irregular pleural thickening and b)left-sided enhancing posterior chest wall invasion in a patient with malignant pleural mesothelioma; c) coronal MRI thorax image of the samepatient, demonstrating the left-sided enhancing pleural thickening and chest wall invasion.

TABLE 1 The four surgical options in malignant pleural mesothelioma, as described by RICE

et al. [74]

Extrapleuralpneumonectomy

En bloc resection of the parietal and visceral pleura with the ipsilaterallung, +/− pericardium and diaphragm

Extended pleurectomydecortication

Parietal and visceral pleurectomy to remove all gross tumour withresection of the diaphragm and/or pericardium

Pleurectomy decortication Parietal and visceral pleurectomy to remove all gross tumour withoutdiaphragm or pericardial resection

Partial pleurectomy Partial removal of parietal and/or visceral pleura for diagnostic orpalliative purposes, but leaving gross tumour behind

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[74]. These include extrapleural pneumonectomy (EPP) and extended pleurectomy decortication (EPD),which aim to achieve maximal macroscopic resection and are nominally curative, and those such as partialpleurectomy or pleurectomy/decortication, which are performed with purely palliative intent [74].

EPP involves en bloc resection of the parietal and visceral pleura along with the ipsilateral lung,pericardium and hemidiaphragm if necessary. EPD is lung-preserving, but attempts to remove all grosstumour with resection of the parietal and visceral pleura and diaphragm and/or pericardium [74].

Although many guidelines recommend maximal macroscopic resection for patients with early-stagemesothelioma, there is a paucity of high-quality evidence to support this. Both of these procedures areassociated with significant post-operative mortality and morbidity, with some studies reporting moralityrates as high as 15% when delivered as part of multimodal therapy [75].

The multicentre Mesothelioma and Radical Surgery (MARS) feasibility trial, which was published in 2011by TREASURE et al. [76] was the first, and, to date, only prospective randomised controlled trial (RCT) toevaluate the efficacy of EPP in addition to chemotherapy alone. Participants were given inductionplatinum-based chemotherapy with subsequent randomisation to either EPP with subsequent radiotherapyor no EPP. Although a feasibility study by design, it suggested that EPP, as part of a trimodality approach,shortened survival compared to chemotherapy alone and had no effect on quality of life. In addition, therewas a high rate of adverse events in the interventional arm, with a post-operative mortality rate of 19%.

Meta-analyses in the past decade have suggested that short-term perioperative mortality is higher in EPPcompared to EPD, with a suggestion that long-term survival is also better in the EPD group [77, 78].Consequently, EPP has largely been abandoned with practice shifting towards the less aggressive EPD [2, 79].

However, there is little high-quality evidence to support the use of EPD. To date, studies evaluating its usehave been observational, with most being single-centre and limited to highly selected patients withearly-stage epithelioid disease. The MARS 2 trial (clinicaltrials.gov identifier NCT02040272), which iscurrently recruiting across the UK, seeks to address this significant gap in the literature by randomisingpatients to EPD or pleurectomy decortication, at the surgeon’s discretion, after chemotherapy inductioncompared to chemotherapy alone.

Pleurectomy decortication and partial pleurectomy, unlike EPP and EPD, do not attempt macroscopiccomplete resection and are debulking procedures. Neither has been shown to improve survival compared tono surgery, but they may improve quality of life. A systematic review by SCHWARTZ et al. [80] revealed eightstudies (total of 432 patients) which evaluated the effect of pleurectomy decortication or partial pleurectomyon quality of life. These procedures were generally thought to improve symptom control and quality of life;however, only one of these studies had a comparator group and there was a reliance on observational data.

The MesoVATS trial by RINTOUL et al. [81] randomised patients to either video-assisted thoracoscopicpartial pleurectomy (VATS-PP) or talc pleurodesis via chest drain. This demonstrated that VATS-PP didnot confer a survival benefit compared to standard talc pleurodesis, which was its primary outcome.However, analysis of secondary outcomes suggested that quality of life, as measured by the EQ-5D, wassignificantly better at 6 and 12 months.

Given the lack of robust data backing surgery in MPM, the British Thoracic Society guidelines do notrecommend surgery outside clinical trials [12], although the American Society of Clinical Oncology guidelinesrecommend maximal surgical cytoreduction in selected patients with early-stage nonsarcomatoid MPM, as partof multimodality treatment, but should not be considered for sarcomatoid mesothelioma [61]. The EuropeanRespiratory Society/European Society of Thoracic Surgeons/European Association for Cardio-Thoracic Surgery/European Society for Radiotherapy and Oncology guidelines [62] state that surgery may be appropriate for asubgroup of carefully selected patients, with extended EPD rather than EPP, but that radical surgery is notrecommended for sarcomatoid or predominantly sarcomatoid mesothelioma outside clinical trials. The authors’view is that EPP should never be offered for mesothelioma except in highly selected circumstances, and thatsurgery in general should be offered only in clinical trials where available, and in highly selected patients if trialsare not recruiting. One may take the view that the collated data on surgery suggest that less surgery is better.

Systemic anticancer therapyThe results of chemotherapy have traditionally been thought to be disappointing due to low response ratesand the systemic toxicity associated with treatment regimens. However, it is one of the only treatmentmodalities that has been shown to improve survival in MPM.

Current first-line therapy stems from a 2003 study by VOGELZANG et al. [5]. They randomised 456treatment-naïve patients to cisplatin with pemetrexed or cisplatin alone and demonstrated thatcombination therapy improved median survival from 9.3 months to 12.1 months (p=0.02), with

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significantly higher response rates to treatment. A second RCT by VAN MEERBEECK et al. [82] also evaluatedthe addition of a folate antimetabolite, raltitrexed, with single-agent cisplatin in 2005. This providedsimilar results with improved median survival, progression-free survival and response rate compared tocisplatin monotherapy. However, the recruitment of this study fell short of the revised accrual targetrecommended by its independent data monitoring committee.

A nonrandomised open-label study in 2008 evaluated the safety and efficacy of carboplatin in combinationwith pemetrexed compared to that of cisplatin. Although the data should be interpreted with caution,carboplatin demonstrated a similar response rate and median survival compared to cisplatin [6]. It is generallybetter tolerated and is now considered an option for patients who are thought to be unfit for cisplatin.

Treatment response in sarcomatoid mesothelioma is poorly reported, but appears to be lower forsarcomatoid mesothelioma, with four (22%) out of 18 patients with sarcomatoid mesothelioma respondingto treatment with cisplatin/pemetrexed combination [5, 83].

Second-line therapyThe evaluation of second-line therapy has largely been limited to phase II trials and the optimalsecond-line agent is not known. A systematic review by BUIKHUISEN et al. [84] conducted in 2015 suggestedthat single-agent vinorelbine or pemetrexed were reasonable options for those who had relapsed onfirst-line therapy. Only two of the included 10 studies were phase III trials and one of these did not showany benefit in progression or overall survival with the addition of thalidomide. The other, by JASSEM et al.[85], demonstrated that pemetrexed provided improved response rate and disease control compared to bestsupportive care in patients who had not received prior pemetrexed. No benefit in overall survival wasdemonstrated; however, the authors hypothesise that this may reflect the use of post-discontinuationchemotherapy in the best supportive care arm.

Given the paucity of data, patients with adequate performance status should be enrolled in clinical trialswhere possible.

Targeted therapiesThe addition of bevacizumab, a vascular endothelial growth factor inhibitor, to cisplatin and pemetrexedas first-line therapy was evaluated by ZALCMAN et al. [7] in a randomised, controlled open-label phase 3trial. 448 individuals with unresectable disease from centres across France were randomised to receivecisplatin and pemetrexed with or without bevacizumab. The addition of bevacizumab extended mediansurvival from 16.1 months to 18.8 months (p=0.167). A higher rate of adverse events was noted in thebevacizumab group; however, the majority of these were expected, such as higher rates of thromboticevents and hypertension [7].

The past few years have witnessed the publication of data on the utility of immunotherapy in thetreatment of mesothelioma. The DREAM study (Durvalumab with First-Line Chemotherapy inMesothelioma) investigated the addition of the programmed death ligand 1 inhibitor durvalumab tostandard-of-care chemotherapy [86]. The primary end-point of progression-free survival was 57% at6 months, which is encouraging, but also suggests early escape from immune control. These results haveled to an international randomised phase 3 study, which is currently ongoing.

A number of other targeted agents are also being evaluated for use in mesothelioma, but thus far datahave largely been limited to small series and results have been modest. The trial CheckMate743 iscurrently testing whether there is a benefit of combination immunotherapy (nivolumab plus ipilimumab)over standard chemotherapy. Early results presented by Baas et al. at the IASLC World Conference onLung Cancer in August 2020 were encouraging, and reported that nivolumab and ipilimumab innonepithelioid mesothelioma resulted in 18.1 months overall survival compared to 8.8 months overallsurvival with chemotherapy (hazard ratio 0.46, 95% CI 0.31–0.68). Similarly, the UK’s CONFIRM study,which will randomise 336 patients with progression to nivolumab or placebo after at least two treatments,is currently recruiting and due to be completed by mid-2021 (ClinicalTrials.gov identifier NCT03063450).

RadiotherapyRadiotherapy has been used both for focal palliation and as part of multimodality regimens aftercytoreductive surgery to limit disease relapse in the ipsilateral hemithorax. However, there are limited datato support the effectiveness of this approach or its impact on survival [12].

A number of centres have reported extremely encouraging overall survival with adjuvantintensity-modulated radiotherapy following EPP or EPD [87]. However, these case series findings have notbeen replicated in larger multicentre trials and the authors of these studies have subsequently concludedthat the routine use of hemithoracic radiotherapy cannot be justified [88, 89].

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Radiotherapy is also used with palliative intent to reduce chest wall masses or alleviate pain associatedwith rib invasion or infiltration of intercostal nerves. However, the evidence for this has been limited withmost of the published data coming from retrospective case series or single-arm prospective studies.Furthermore, responses are often not durable, with studies demonstrating pain recurrence within theprevious radiotherapy field and typically within 3 months of treatment [90].

The largest of these studies, the single-arm SYSTEMS study, recruited 40 patients from three UK centres.It reported that a third of patients had a significant improvement in their pain at 12 weeks, with 12.5% ofpatients experiencing a complete response [91]. SYSTEMS-2, a multicentre phase II randomised doseescalation study commenced in 2016 and is due to report shortly (isrctn.com identifier ISRCTN12698107).

Control of associated pleural effusionsThe majority of patients with mesothelioma develop a pleural effusion during their disease course [2].Traditional management has involved admission to hospital and intrapleural administration of sterile talcthrough a standard chest tube [92]. However, talc pleurodesis has been shown to fail in preventingrecurrent effusions at 30 days in ∼30% of cases [93], and patients with MPM have lower rate of talcpleurodesis success compared with nonmesothelioma patients (73% versus 85%, p=0.02) [94]. This may berelated to higher rates of nonexpandable lung in MPM patients, greater pleural tumour bulk in MPMleading to decreased area of normal pleura available for pleurodesis success. This management paradigm isalso associated with increased healthcare costs [95].

At least three large high-quality RCTs have demonstrated that indwelling pleural catheters (IPCs) provideequivalent control of dyspnoea compared to talc pleurodesis and are associated with reduced inpatient stay[96–98]. In a trial comparing IPC with talc pleurodesis, 38 patients with mesothelioma were included, andhad IPC insertion (n=20) or talc pleurodesis (n=18): effusion-related hospital stay was 1 versus 3 days,respectively (p=0.003) [99]. They are now considered to be effective first-line treatment, in addition to thestandard indication of trapped lung [96, 99, 100]. Their use is increasing worldwide, and compared toconventional treatment with talc pleurodesis, IPC insertion is associated with reduced hospital stays andfewer subsequent pleural procedures [99].

However, the burden of IPC use both on patients and health services is often not fully recognised [101].Rates of nonserious complications are high in most IPC studies and successful use of IPCs is reliant onadequate community follow-up and support [102].

A number of RCTs have explored optimal IPC strategies. These have shown that more aggressive drainagestrategies leading to higher rates of pleurodesis, which would facilitate IPC removal, without leading toimproved breathlessness [103–105]. Notable among these was the IPC-Plus study by BHATNAGAR et al.[105]. This randomised 154 patients (n=23 mesothelioma) to either talc slurry or placebo deliveredthrough the indwelling pleural catheter. They demonstrated that at day 35 the pleurodesis rate in theintervention arm (43%) was significantly higher than that of the placebo group (23%).

Successful pleurodesis may be associated with a survival benefit. In a study of patients with MPEundergoing talc pleurodesis, two datasets were analysed, with MPM being the commonest malignancy inboth datasets: 22 (36.6%) out of 60 patients in dataset 1 and 104 (40%) out of 259 patients in dataset 2.Pleurodesis success, defined as absence of the need for further therapeutic pleural procedures at 3 monthsafter intrapleural talc administration, was associated with improved survival (adjusted odds ratios fordecreased survival with pleurodesis failure 2.9 (95% CI 1.1–7.5, p=0.03) and 1.6 (95% CI 1.1–2.4, p=0.02),respectively) [106]. Successful pleurodesis is more likely with talc, especially via a large-bore chest drain,than with an IPC (∼70–75% versus 51%, respectively [93, 96].

Multidisciplinary team careThe modern management of mesothelioma is delivered through multidisciplinary teams. These draw onskills from across the healthcare spectrum and aim to streamline the often protracted diagnostic andtherapeutic pathways that patients experience.

While there is no set template for this, most larger multidisciplinary team meetings will have access toinput from pleural teams, thoracic surgery, thoracic radiology, pathology and oncology. Given theoutcomes of mesothelioma, palliative care input is crucial to resolve complex physical symptoms,psychosocial or spiritual needs; however, routine early referral does not appear to confer any benefit inhealth-related quality of life or mood [107].

Mesothelioma specialist nurses have an integral role in providing and coordinating the care needs ofpatients and their carers.

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ConclusionDespite asbestos use being banned in many countries, new cases of MPM are still being diagnosed becauseof the lag between exposure to asbestos and diagnosis of MPM. In addition, although asbestos is the mostcommon factor to be associated with MPM, other factors may also be involved including exposure toerionite and radiation, and genetic factors.

The management of MPM can be challenging because of paucity of effective treatments that prolongsurvival significantly. Cisplatin and pemetrexed combination, with addition of bevacizumab whereavailable, is first-line treatment, but only in patients with adequate performance status. The outcomes ofsurgery remain controversial and hopefully, ongoing trials will shed light on whether certain surgicaloptions will be beneficial in select patient groups.

Conflict of interest: R. Asciak has nothing to disclose. V. George reports personal fees from Teva UK Ltd/HaymarketMedia Group Ltd, outside the submitted work. N.M. Rahman has nothing to disclose.

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